Bcl-xL Inhibition Disrupts p27 Stability and Promotes Senescence Escape: Insights for Cancer Senotherapy

Purpose: Cellular senescence serves as a double-edged sword in oncology, acting as a tumor suppressor and a promoter of a pro-tumorigenic environment post-chemotherapy, necessitating targeted removal strategies. To investigate whether inhibition of Bcl-xL (a key anti-apoptotic protein and senescent cell survival factor) leads to therapeutic failure by enabling senescent tumor cells to resist apoptosis, re-enter the cell cycle, and potentially drive tumor progression. Methods: We utilized pharmacological Bcl-xL inhibitors and shRNA-mediated Bcl-xL knockdown to disrupt Bcl-xL function in senescent tumor cells. The effects on cell fate, cell cycle regulators, and associated molecular pathways were analyzed. Results: Contrary to the expected induction of apoptosis, Bcl-xL inhibition facilitated the cell cycle re-entry of senescent tumor cells. This escape from senescence was driven by a marked reduction in the stability of the cell cycle inhibitor p27. The reduction occurred through increased cytoplasmic localization of p27 and reduced phosphorylation, leading to its proteasome-dependent degradation. Thus, Bcl-xL disruption initiates a pathway enabling senescence escape. Conclusion: Inhibiting Bcl-xL in senescent tumor cells promotes senescence escape rather than apoptosis, representing a significant paradigm shift in understanding senolytic drug mechanisms. These findings reveal the complex dual nature of senescence in cancer and underscore the critical need for careful design when combining senolytic agents with chemotherapeutics to prevent inadvertent tumor cell proliferation.